Method of preparing n-sulphonylureas



Patented Mar. 2, 1943 UNITED STATES PATENT OFFICE v METHOD PREIGABERINASG N-SULPHONYL- V Erich Haack, Radebeui, near Dresden, Germany;

vested in the Alien Property Custodian As a general rule urea derivatives of aromatic sulphonic acids which are substituted at the ni' trogen cannot be prepared in the simple manner of a reaction of ureas upon sulphonyl' chlorides. as it is the case in obtaining the corresponding urea derivatives of the organic carboxylic acids. It is true that hydrogenchloride is split during the reaction, if we attempt such a reaction be tween urea and sulphonyl chloride; still we do not obtain the sulphonylureas, but merely sulphom'c acids alongside of products derived from urea by splitting off water, or products of poly merisation thereof, such as dicyandiamide.

It has now been discovered, that a good yield of the desired N-sulphonylureas may easily be obtained in a roundabout way:

First the corresponding N-sulphonylisoureaalkylethers are prepared, which are then split into N-sulphonylureas and alkylhalides by treatment with hydrogen halides, e. g. concentrated hydro chloric acid. It was further determined that the N-sulfonyl-isoureaalkylethers are quite easily prepared from the sulphonic acid halides, and the corresponding isoureaethylethers. It is surprising that in the reaction there do not arise complications of the type occurring in an attempted transposition between sulphonyl chloride and urea as first mentioned above.

Of course other methods may be used for preparing the sulphonylisoureaalkylethers; for instance-as far as sulphonyl compounds are suited for this purpose-the method described for acylureas by Wheeler and Johnson, American Chemical Journal 24, page 216 (1900), may be applied.

'The N-sulphonylureas result from, sulphonyllsoureaalkylethers having the following general formulae:

R1 o-nn:

RS o,-NC=N--n,

O-Alk wherein R is an aromatic substituent, R1 and R2 are hydrogen, alkyl, aryl or aralkyl, and All; is an alkyl or aralkyl radical. The basic proper ties which these compounds have on account of their isourea constitution, are barely noticeable. The acid properties are more pronounced, if R1 is hydrogen and attaches to the nitrogen atom 8 Claims. (Cl. 260-39737) neighbouring the sulphonyl radical. In that case the compound may be dissolved in a. fairly strong caustic soda solution. But the compounds are not soluble in caustic soda solution, when R1 is alkyl or is not attached to the nitrogen atom neighbouring the sulphonyl radical. reason of this distinction we may separate the isomeric compounds which may be obtained from the mono-substituted isoureaalkylethers substituted by an alkyl radical B32 the corresponding.N-sulphonylureas are StIOHg" 1y acid compounds. Otherwise they are neutral compounds. They are most readily soluble in diluted soda solution, and arethus easily distinguished from the] sulphonylisoureaethers.

The alkali saitsare crystalline compounds, which readily dissolvein water with substantially tral reaction.

Compounds of this invention may be used for technical as well as medicinal purposes. Of particular value are compounds which have amino group in p-position to the SOz-group on the aromatic sulphonyl nucleus and also carry a hydrogen atom on the nitrogen atom which is linked to the sulphonyl radical. These compounds serve as remedies for infectious diseases.

The amino group may be introduced as acylated amino group together with the sui phonic acid component, and subsequently made free by way of saponiflcation. Or it is introduced as a nitro-group which is reduced to an amino group either after the isourea compound or after the urea compound has been prepared.

Emu: 1

N-benzenesulphmwlurea.-62 gr. of isoureamethylethermethylsulphate (from urea and dimethylsulphate) are dissolved in 100 cc. of water and are mixed with 110 gr. of dry potassium carbonate. 60 gr. of benzenesulphochloride are added while the mixture is being stirred well, the

solved in a caustic soda solution and reprecipitated with glacial acetic acid. In the purified state it has a melting point oi 164 165" C.

Splitting on the methyl group 50 gr. of the above unpurified product are heated with 150 cc. of concentrated hydrochloric acid to 60 C. until the evolution of methylchloride, which is very lively at the beginning, has stopped completely. The solid product dissolves clearly during this reaction, but it resolidifies at the end. It is diluted with 250 cc. of water and neutralized with carbonate of soda, being completely dissolved. It is filtered and acidulated with 20 cc. of glacial acetic acid. The product crystallizes out as a white mass and weighs 40 gr. after drying. It m be purified either by dissolving in a soda sol ion and precipitation by acetic acid or by cryst liization from acetone or benzol. The melting oint is 170-171 C.

p-Toluenesulphochl ride and isoureamethylether may be reacted l{pen in like manner and then split by hydrochl ric acid. The same ureas may also be obtained y reacting upon isoureaethylether with benzene-or toiuenesulphochloride, respectively, and by then splitting oi! ethylchloride by means of concentrated hydrochloric acid.

Exam; 2

p-Aminobenzenesulphonglurea.300 gr. anhydrous potassium carbonate, 300 cc. oi saturated potassium carbonate solution, and 150 gr. of acetylsulphanilylchloride are mixed in several portions with 125 gr. isoureamethylethermethylsulphate in a'closed mixing apparatus, and are then stirred for twelve hours. 400 cc. oi. water are added and the product is filtered by suction. The moist precipitate is worked through with 800 cc. of a 4% caustic soda solu tion, sucked on from the insoluble residue and washed with water. After drying 20 gr. of the insoluble acetylsulphanilylchloride are recovered, which have not been reacted upon. The clear solution is precipitated with 100 cc. of glacial acid and is sucked on after a short interval. 100 gr. of raw N-(acetylsulphanilyD-isoureamethylether are obtained, having a melting point of 188-198 C. The melting'point of the productis 208-209 C., after it has been repeatedly dissolved in caustic soda solution and reprecipitated with glacial acetic acid.

Splitting 017 the methyl group and the acetul group Both these reactions take place at once, ii 100 gr. of theabove unpurified-productare heated in 150 cc. of concentrated hydrochloric acid for an hourand a half to 60 C. The originally solid mass goes into clear solution, but finally crystallizes again, after the lively evolution of methylchloride is finished. The product is dissolved in water and neutralized by carbonate ct soda; alter-filtering it is precipitated by 49 cc. of sla cial acetic acid. Approximately 75 gr. of N- sulphanilylurea are obtained.

Potassium salt cipitated in fine flakes and may be crystallized from hot water.

The colorless flakes readily dissolve in cold water with a fully neutral reaction (pH='l).

A pure p-aminobenzenesule phonylurea, which decomposes when melted at l49-154 C., is obtained from the pure potassium salt by precipitation with acetic acid.

The ethyl-, propylor higher ethers of the acetylsulphanilylisourea may be prepared in like manner and will yield the same urea. when treated with hydrochloric acid, ethylchloride, I

propylchloride etc. being split oil, respectively.

. Emmet! 3 r N -(p-aminobenzenew1phonyl) N'N -dimethylurea.300 gr. of potassium carbonate, .300 cc.

Splitting 01) the methylether group 90 cc. of concentrated hydrochloric acid are poured into'90 gr. 0! the foregoing product.

Methylchloride is immediately given oil and the process is completed at 45 C. in about 20 minutes. The mass which had dissolved at the beginning is solidified. Water is added and after cooling the product is washed with water. The product is 72-75 gr. of crude acetyl-sulphaniiyl dimethylurea.

, Splitting of the acetyl group This is effected by heating with 2 mols caustic soda in watery solution to -90 C. and o-aminobenzenesulphonyldimethylurea is obtained whichmeits at 158-161 C. This is accompanied by decomposition, the residue resolidifies at 171-173 C. and melts again at 253'-255 .C. The sodium salt forms fine needles and is most readily dissolved in water with neutral reaction (pH=7). Similarly other unsymmetrical dialkyl-substituted p-acetylaminobenzenesulphonylureas. and p-aminobenzenesulphonylureas may be prepared, such as the corresponding N'N'-diethylurea, the N'N'-dibutylurea or higher dialkyl derivatives; likewise mono-substituted ureas, e. g. the corresponding N'-monomethyland N'- monobenzyiand N'-monophe nylurea. Instead of isoureamethyiether we may use with like success other alkylethers, e. g. ethylor propylether. Instead of the concentrated hydrochloric acid diluted hydrochloric acid or gaseous hydrogen chloride maybe used, just as well' as hydrobromic or hydroiodic acid. a f I Havingthus given a careful outline of my invention in detail, yet I do not wish it to be limited thereby, except as the state of the art and the appended claims mayrequiraior it is obvious that various modifications and changes may be made in theform of embodiment of my in vention, without departing from the spirit and scope thereof.

What I claim is: l. The process of preparing N-sulphonylureas of the formula 11-. nm-ar l-s 0,-NHC -N\ wherein aryl represents a benzene-nucleus, the amino radical H2N stands in p-position to the sulphonyl group, wherein R2 stands for a radical selected from the group consisting of hydrogen and alkyl, and wherein R3 stands for a radical selected from the group consisting of hydrogen, alkyl and aryl, comprising treating a corresponding N-acetyl-sulphanilyl-isoureaalkylether with a hydrogenhalide, until the halide of the alkyl radical of the ether is split off.

2. The process of preparing N-sulphonylureas of the formula R2 H,N'arylS O -lNH-C o:-'

wherein aryl represents a benzene nucleus, the amino radical HzN stands in p-position to the sulphonyl group, and R2 and R: standfor radicals selected from the group consisting of hydrogen and alkyl, comprising treating a corresponding N-sulphonylisoureaalkylether with concentrated hydrochloric acid under heat at temperatures ranging up to 100, until the alkyl radical of the ether has been split off in the form of alkyl chloride.

3. The process of preparing N-sulphonylurea of the formula wherein aryl is a benzene nucleus, comprising wherein aryl is a benzene nucleus, comprising treating a corresponding N-acetyl-sulphanilylisoureaalkylether with a hydrogenhalide until the halide of the alkyl radical or the ether is split off, and saponifying the acetyl radical.

5. The process of preparing N-sulphonylurea of the formula HzN-8.ry1SO2-NHCONH-Rz wherein aryl is a benzene nucleus, and wherein R2 means an alkyl radical, comprising treating wherein aryl is a benzene nucleus, and wherein R2 and R3 stands for alkyl, comprising treating a a corresponding N-acetyl-sulphanilyl-isourealkylether with a hydrogenhalide until the halide of the alkyl radical of the ether is split off, and saponifying the acetyl radical.

7. The process of preparing N-sulphonylurea of the formula wherein aryl is a benzene nucleus, and wherein R2 and R3 stand for alkyl, comprising treating a corresponding N acetyl-sulphanilyl isoureaalkylether with a hydrogenhalide until the halide of the alkyl radical of the ether and the acetyl radical are split off.

8. The process of preparing N-sulphonylurea of the formula wherein aryl is a benzene nucleus, and wherein R2 and R3 stand for alkyl, comprising treating a corresponding N-acetyl-sulphanilyl-isoureaalkylether with a hydrogenhalide until the halide of the alkyl radical of the ether is split off, and saponifying the acetyl radical.

ERICH HAACK. 

